1. Field of the Invention
This invention concerns an enema solution or suspension which is suitable for rectal administration of 5-.[.aminosalicyclic.]..Iadd.aminosalicylic .Iaddend.acid (5-ASA) in mammals. The present enema solutions are useful in the treatment of bowel diseases, in particular, ulcerative colitis, Crohn's disease located in the colon and .[.proctoigmoiditis.]. .Iadd.proctosigmoiditis.Iaddend..
2. State of the Prior Art
.[.Salicyclazosulfapyridine.]. .Iadd.Salicylazosulfapyridine .Iaddend.(SASP) has for a long period of time been a cornerstone in the treatment of ulcerative colitis and has been used in various pharmaceutical dosage forms including enemas. When SASP reaches the colon, it is split by bacteria into sulfapyridine (SP) and 5-ASA and, as explained in detail in copending U.S. application Ser. No. 555,533, filed Nov. 28, 1983, which is a continuation application of Ser. No. 270,517, filed May 29, 1981, now abandoned, and based on International Application No. WO81/02671, both of which are incorporated by reference, most experts now hold the active moiety of SASP to be 5-ASA.
Azad Khan et al, Lancet, 1977, pp. 892-95, compared suspensions of SASP, SP and 5-ASA administered rectally and concluded that the therapeutic active moiety was 5-ASA and that SP only acts as a carrier to ensure that 5-ASA is not released until it has reached the colon. Stability tests showed that SASP and SP suspensions were stable at room temperature while the 5-ASA suspension showed some decay and had to be made up in fresh batches every three months and stored in a refrigerator until used.
Similar observations were made by Campieri et al, Lancet, Aug. 8, 1981, pp. 220-21, who carried out a comparison trial between 5-ASA and hydrocortisone. Since 5-ASA turned brown in solution, they added charcoal to the hydrocortisone as coloring agent in order to ensure double-blindness.
While enemas containing 5-ASA have thus proved useful in the treatment of ulcerative colitis, their limited stability is a major problem and a solution to this problem would be of great advantage.
It has now been discovered that the desired stability can be obtained by packaging an aqueous solution or suspension of 5-ASA or a pharmaceutically acceptable salt or ester thereof being contained in a plastic bottle under an inert gas in a diffusion-tight package impervious to light in the same inert gas as was used in the plastic bottle.
The 5-ASA solution or suspension should further contain a chelating agent, an antioxidant and a buffer in order to provide a pH value of from 4 to 7.
The presence of the same inert gas on both sides of the plastic bottle provides an equilibrium which effectively cooperates with the various stabilizers and the diffusion-tight light-impervious package and provides a stability of a year or more.